What the Anesthesiologist Should Know before the Operative Procedure

General. Pheochromoctyoma (Pheo) is a rare but potentially life-threatening neuroendocrine tumor that arises from the chromaffin cells of the adrenal medulla (in 80% of cases) or extra-adrenal paraganglionic tissue (in 20% of cases). The latter, classified as extra-adrenal paragangliomas, occur anywhere from the base of the skull to the pelvis. Only cells that stain positive for chromaffin secrete catecholamines. These most commonly arise around renal vessels or the organ of Zuckerkandl, which displays the largest collection of chromaffin tissue. These tumors derive their name from the positive immunostaining for chromagranin A.

Epidemiology. The incidence of pheochromocytoma in the general population has been estimated to be 0.3 per million per year. In children, the incidence of benign pheo is 1 per 10 million and of malignant pheo, 1 per 50 million. Approximately 10-20% of all pheos are diagnosed in childhood at any age from neonates to adolescents, with an average age at the time of onset of 11 years. The sex distribution in childhood shows a preponderance of males whereas the distribution during the reproductive years shows a preponderance of females. The net effect is an equal distribution in the sexes. In contrast to adults, pheochromocytomas in children are more often bilateral, multiple in number and extra-adrenal.

Most pheochromocytomas are benign, with only 5-10% reported as malignant (although some have reported malignancies as great as 50%). Malignancies have been reported in the bones, lungs, lymph nodes and liver. The diagnosis is confirmed by the presence of chromaffin cells. The SDHB mutations are the most likely to metastasize. These malignancies are more likely to secrete dopamine than the benign tumors. The 5 year survival of metastatic pheo is 50%. These tumors have no effective treatment: 80% of adults have improved with radical surgery and 131I MIBG therapy, although only 5% go into remission.

In childhood, 40% of pheochromocytomas are inherited, the pattern of inheritance being autosomal dominant. The remaining 60% occur sporadically in the population. Four hereditary syndromes are associated with pheochromocytomas: multi-glandula multiple endocrine neonplasia type 2 (MEN), von Hippel Landau type 2, neurofibromatosis 1, and paraganglionic syndromes. Two additional (non-hereditary) syndromes have been associated with pheochromocytomas: Tuberous sclerosis and Carney's triad.

The gene defect responsible for the MEN syndromes is located on chromosome 10q11.2. MEN type 2A (Sipple syndrome) includes medullary thyroid cancer, parathyroid adenoma, and pheochromocytoma. MEN type 2B includes medullary thyroid cancer, multiple neuromas, Marfan habitus and pheochromocytoma. pheochromocytomas associated with MEN secrete both epinephrine and norepinephrine. These tumors appear bilateral in 50-80% of cases, but rarely metastasize.

von Hippel Lindau syndrome type 2 (type 1 does not involve pheochromocytomas), is subgrouped as: a, b and c. The gene mutation responsible for von Hippel Landau is located on 3p25-26. Although all three subgroups of this syndrome include pheochromocytoma in 10-20% of children, they are distinguished by the other organ involvement: type 2a involves hemangioblastomas of the central nervous system, endolymphatic sac tumors and epidymal cystadenomas: type 2b involves all the organs in type 2a as well as renal cell and pancreatic cysts and tumors. The only tissues associated with Type 2c are pheochromocytomas. When associated with this syndrome, pheochromocytomas predominantly secrete norepinephrine. These tumors occur bilaterally in the adrenal glands, but rarely metastasize.

Neurofibromatosis type 1 involves neurofibromas and cafe-au-lait spots. The genetic mutation is found on chromosome 17q11.2. Pheochromocytomas occur in <5% of children with neurofibromatosis.

Paraganglioma syndromes arise from mutations in the gene that codes for succinate dehydrogenase on cytochrome oxidase II in the respiratory chain of mitochondria. Two genetic mutations involve pheochromocytomas: subgroup B, which is coded on chromosome 1p 36 and subgroup D, which is coded on chromosome 11q23. These mutations present with paragangliomas of the adrenal, extra-adrenal and head and neck regions. Subgroup B occurs more commonly in children (~20% of pheochromocytomas bear this mutation) with a 30-50% metastatic rate for these tumors. Subgroup D is inherited strictly along patternal lines.

Tuberous sclerosis presents with the clinical findings of epilepsy, neurocognitive dysfunction, polycystic renal disease and retinal phakomas. Tuberous sclerosis arises from two gene mutations located on chromosomes 9q34 and 1613.3, that code for the production of hamartin and tuberin, respectively. The wild types of these proteins suppress tumor production.

Carney's triad, which usually occurs in young women, is comprised of gastric leiomyosarcoma (currently recognized as gastrointestinal stromal tumors), pulmonary chondroma and extra-adrenal pheochromocytoma.

Presenting signs and symptoms. Pheochromocytomas can secrete epinephrine, norepineprhine and/or dopamine. Most of these tumors secrete norepinephrine as the predominant hormone. Only 10-20% secrete epinephrine and dopamine as the predominant hormones. Hypertension is the most common presenting sign of this tumor. It is often accompanied by regular, intermittent headaches that are associated with nausea and vomiting. The classic triad of headaches, sweating and palpitations along with hypertension constitute the presenting signs in >90% of children with pheochromocytomas. Sustained hypertension is present in 60-90% of cases in children but is not a requirement for the diagnosis. In fact, there is no relationship between circulating catecholamine concentrations and overt symptoms. Epinephrine-secreting tumors can present as circulatory shock due to decreased intravascular volume as a result of sustained high concentrations of catecholamines and their effects on vascular resistance. Tumors that secrete predominantly dopamine do not usually present with hypertension.

Other presenting findings that occur in children include weight loss, nausea and vomiting, polyuria, visual disturbances and anxiety. Presenting signs include pallor, orthostatic hypotension, tremor and syncope as well as abdominal pain, diarrhea other gastrointestinal manifestations, hyperglycemia, low-grade fever and behavioral disturbances.

On occasion, triggers of catecholamine release may include anesthesia, micturition (as in a urinary bladder pheochromocytoma), foods, and drugs such as metoclopramide, tricyclic antidepressants, glucagon and radiocontrast dye.

1. What is the urgency of the surgery?

What is the risk of delay in order to obtain additional preoperative information?

i. Emergent, Urgent Surgery. Emergency surgery is a hotly debated subject in the case of patients with pheochromocytomas. The vast majority of these tumors are scheduled for elective removal after alpha-adrenergic blockade has been pharmacologically established. Rare instances of multi-organ failure from pheo-associated "catecholamine crisis" have been reported. The crisis includes cardiomyopathy and congestive heart failure, hypertension, encephalopathy (with seizures), fever, and end-organ damage that required life-saving resection of the tumor to prevent a fatal outcome. In such situations, aggressive alpha blockade while concurrently supporting an adequate cardiac output take precedence.

Pheochromocytomas have been described as the great mimics, giving support to a differential diagnosis that includes acute coronary infarction, carcinoid tumor, thyroid storm and cocaine (other amphetamine-like drugs) overdose. In other emergent circumstances, surgery undertaken for acute appendicitis with an undiagnosed pheochromocytoma has been terminated prematurely once the diagnosis of a pheochromocytoma was strongly suspected. Conservative management of the acute appendicitis was undertaken while the pheochromocytoma was investigated and the patient was alpha-blocked.

ii. Elective. Surgicalresection of pheo is optimally managed on an elective basis, after the child's medical status has been investigated, medical conditions are stabilized, the tumor location has been investigated and the alpha-adrenergic system is completely blocked. It must be emphasized that beta-blockade should NEVER be introduced until alpha-blockade has been well-established because this could result in unopposed paroxysmal systemic hypertension, acute coronary or stroke signs and death. Therefore, preoperative management requires the institution of a non-competitive alpha-blocker such as phenoxybenzamine. Phenoxybenzamine irreversibly alkylates alpha-adrenergic receptors preventing an alpha-adrenergic medicated parxoymal increase in blood pressure. The disadvantage of irreversibly blocking alpha-adrenergic receptors is that reactive hypotension may follow removal of the tumor. Competitive alpha-adrenergic blockade with doxazosin, which has a brief duration of action compared with phenoxybenzamine, may be displaced from the alpha receptors by increased concentrations of circulating catebcholamines. Alpha-blockade has reduced perioperative complications during pheochromocytoma resection from 60% to 3%. Beta-blockade may be initiated once alpha-adrenergic receptor blockade has been established.

2. Preoperative evaluation

N/A

3. What are the implications of co-existing disease on perioperative care?

Perioperative evaluation- These children should be transferred from the pediatric intensive care unit where they have been managed for the preceding two weeks to block their alpha1 adrenergic receptors. The pre-treatment blood pressure should be compared to their supine blood pressure. The current blood pressure (and heart rate) should be within normal limts. Heart rate should also be normal or at least moving in that directions as fluids have been infused. A recent electrocardiogram and echocardiogram should be reviewed to assess the arrhythmias and myocardial function. Thyroid function tests and serum calcium and blood glucose concentrations should be evaluated as indicated by the associated endocrinopathies present. The subject should be examined for cafe au lait spots if neurofibromatosis is suspected. That being the case, a history and physical examination should focus on the presence of neurofibromas particularly for a pulmonic flow murmur or a change in the child's voice suggestive of an intracardiac or laryngeal neurofibroma.

Perioperative risk reduction strategies- Alpha-adrenergic blockade should be established to reduce the perioperative surgical risks. Preparation for general anesthesia with invasive arterial and central nervous system catheters, transesophageal echocardiogram as needed should be available. Infusions to manage hypertensive crises should be available including sodium nitroprusside, magnesium sulfate and esmolol.

b. Cardiovascular system

Acute/unstable conditions: Arrhythmias and myocardial dysfunction should be resolved with using alpha-adrenergic blockade and inotropes as required. Orthostatic hypotension is undesirable preoperatively: fluid boluses should be administered to render the child euvolemic.

c. Pulmonary

N/A

d. Renal-GI:

N/A

e. Neurologic:

N/A

f. Endocrine:

Adrenal.

Hypersecreting adrenal or extra-adrenal pheo should be identified preoperatively and alpha-adrenergic receptors blocked before undertaking general anesthesia.

g. Additional systems/conditions which may be of concern in a patient undergoing this procedure and are relevant for the anesthetic plan (eg. musculoskeletal in orthopedic procedures, hematologic in a cancer patient)

N/A

4. What are the patient's medications and how should they be managed in the perioperative period?

N/A

h. Are there medications commonly seen in patients undergoing this procedure and for which should there be greater concern?

Preoperative strategies to control blood pressure:

All children with pheochromocytoma should be alpha-blocked before undertaking surgery to remove the tumor to attenuate fluctuations in systolic blood pressure during tumor manipulation. Although alpha adrenergic blockade has led to a 20-fold reduction in perioperative complications during pheochromocytoma resection, there is neither a consensus on the optimal strategy to achieve alpha blockade nor metrics published to confirm that alpha adrenergic blockade has been achieved. As a result, much of the preoperative treatment is empirical. The most widely used alpha1-blocking agent is phenoxybenzamine, an alpha1 adrenergic-blocking agent that irreversibly alkylates the alpha receptors. The only means to offset the effects of phenoxybenzamine at the alpha-receptor is by the synthesis of new alpha adrenergic receptors. As a result, alpha-blockade with phenoxybenzamine may increase the risk of post-tumor resection hypotension, until receptors are repopulated. Alternatively, a competitive alpha-adrenergic blocking agent, doxazosin, has been studied. This agent blocks alpha1 receptors, although increasing concentrations of catechoamines such as occurs during induction of anesthesia or tumor manipulation, may displace doxazosin rendering the alpha adrenergic receptors available to respond.

Phenoxybenzamine may be administered orally or intravenously preoperatively to achieve alpha-blockade. The onset of the blockade after oral administration begins slowly, taking up to ~24 hours. Oral bioavailability of phenoxybenzamine is 20-30%. Dosing follows a range between 0.25 and 1.0 mg/kg orally, although doses as great as 2 mg/kg have been used. Children have been treated for 3-15 days with oral phenoxybenzamine before commencing surgery, although there is no means to reliably assess alpha blockade. Some have recommended that alpha blockade has been achieved when the (systolic) blood pressure has returned to within normal limits for the child's age. Alternately, intravenous phenoxybenzamine has been used to more rapidly and perhaps reliably block alpha1 receptors, although aggressive monitoring for peripheral vasodilatation, decreases in blood pressure and relative hypovolemia must be followed until the hemodynamics have equilibrated. Hypotension, a direct consequence of alpha-adrenergic receptor blockade, can be attenuated by the judicious use of intravenous balanced salt solutions and augmenting the sodium intake in the diet.

Beta blockade should not be commenced until alpha blockade has been established. A reflex tachycardia may be expected once alpha blockade has commenced. This should be treated with intravenous fluids to restore euvolemia. Beta blockade should not be introduced until ventricular dysfunction has been ruled out.

Alpha-methyl paratyrosine (metirosine), which blocks catecholamine synthesis, has been used preoperatively in adults. Retrospective studies suggest a reduced need for antihypertensives although this requires confirmation in children and in prospective studies.

i. What should be recommended with regard to continuation of medications taken chronically?

j. How To modify care for patients with known allergies -

l. Does the patient have any antibiotic allergies? (common antibiotic allergies and alternative antibiotics)

N/A

m. Does the patient have a history of allergy to anesthesia?

Malignant hyperthermia:

Documented- avoid all trigger agents such as succinylcholine and inhalational agents:

Proposed general anesthetic plan:

Insure MH cart available:

[- MH protocol]

Family history or risk factors for MH:

Local anesthetics/ muscle relaxants:

5. What laboratory tests should be obtained and has everything been reviewed?

Laboratory findings. Biochemical testing for pheochromocytoma should be performed in children present with signs suggestive of pheochromocytoma, as well as in those who are predisposed to pheochromocytoma or have a recurrence. The most accurate biochemical tests for pheochromocytoma are free plasma metanephrine and normetanephrine concentrations and 24 hour urine for fractionated metanephrines, although even these tests are not without problems. These tests have supplanted the 24 hour urinary and plasma epineprhine, norepinephrine and dopamine and the degradation product, urinary vanillyl mandelic acid. The vanillyl mandelic acid values for sensitivity and specificity are 64% and 95% respectively. Reference standards for metanephrine must be adjusted for the child's age because the concentrations may be as much as 33% less than those in adults. The current tests are much more reliable than older methods for determining pheo risk, such as vanillylmandelic acid concentration. Plasma catecholamine concentrations correlate well with the urine concentrations during sustained tumor catecholamine secretion, although they may be exaggerated during episodes of cardiovascular instability. The test with the greatest sensitivity for normetanephine and metanephrine is the plasma concentration in both sporadic and familiar pheochromocytoma . Plasma metanephrines are present in 99% of sporadic pheochromocytomas. However, this test may be difficult to perform in children because they must remain supine and relaxed for 30 minutes before sampling. The presence of increased urine and plasma catehcolamine concentrations can be attributed to numerous physiologic and pathologic conditions, as well as to medications (eg., acetaminophen, tricyclic antidepressants, beta blockers and calcium channel blockers). However, when the upper reference limits are adjusted, sensitivities of 100% and specificities of 80-94% can be obtained (sensitivities for familial forms are less than for sporadic forms; specificities are reverse). Concentrations of metanephrine and normetanephrine (as determined by high pressure liquid chromatography) that exceed the 99%ile upper limit for normals and thus suggest a "likely" diagnosis of a pheochromocytoma are: blood - free metanephrines >0.42 nmol/L and normetanephrine >1.4 nmol/L; urine - metanephrine >2880 nmol/24h and normetaneprhine >6550 nmol/24h. In some cases, the increase in the biochemical tests to confirm the presence of a pheochromocytoma is borderline. In such cases, oral clonidine may be administered to perform a suppression test, by suppressing the release of norephinephrine. If clonidine suppresses the concentration of plasma normetanephrine >40% below the upper reference limit, then a diagnosis of a pheochromocytoma may be excluded. Caution should be exercised when administering clonidine as alpha2 agonists may cause substantial hypotension and bradycardia in children. Suppression tests are infrequently used today with the sensitivity and specificity of the current catecholamine assays.

Hemoglobin levels: Preoperative hemoglobin and hematocrit should be determined to gauge the adequacy of fluid replacement during alpha blockade.

Electrolytes: Careful examination of the biochemical profile preoperatively will confirm the involvement of other organs. Hypokalemia may be present if hyperaldosteronism is diagnosed. With the excess catecholamine concentrations associated with pheochromocytomas, an increased fasting glucose concentration or an abnormal glucose-tolerance test may be present. This may be exacerbated by hypo-insulinemia due to alpha-adrenergic activity that suppresses pancreatic insulin release. Testing should be undertaken for hypercalcemia to determine whether the parathyroid glands are involved pointing towards MEN syndrome.

Cardiac evaluation: Chronic exposure to increased catecholamine concentrations may lead to a cardiomyopathy, congestive heart failure and arrhythmias. Preoperative investigations should include electrocardiogram, chest X-ray and an echocardiogram. A cardiomyopathy and reduced ejection fraction should be optimized medically before embarking on general anesthesia. Transesophageal echocardiography and central venous pressure and arterial pressure monitoring may be indicated.

Imaging: Once the biochemical diagnostics have been completed and the presence of a pheo confirmed, the tumor (s) must be located. The most common location for these tumors in children is in the abdomen, both within and without the adrenal gland. Currently, computed axial tomography (CAT) and magnetic resonance imaging (MRI) are used to locate these tumors in children. Current CAT scanning techniques are very rapid, but they expose the children to radiation. MRI is a slower study, avoids radiation risk but often requires a general anesthetic. The accuracy of locating a pheochromocytoma with a CAT scan is >96% and with an MRI is 90-100%. However, both the CAT scan and MRI may, on occasion, have difficulty distinguishing a pheochromocytoma from other intra-abdominal lesions, especially when the tumors are <1 cm in diameter. For small tumors or for extra-adrenal tumors, a supplementary radiological investigation known as the 123I- metaiodobenzylguanidine (MIBG) test may be used. Studies with MIBG yield positive responses with both pheochromocytomas and neuroblastomas, necessitating additional studies to distinguish the two. MIBG uptake by the tumor may be impaired in the presence of labetalol and tricyclic antidepressants. Although metastic paragangliomas may lose their ability to take up MIBG, the combination of a positive MRI and MIBG uptake usually confirms the diagnosis. In cases where MIBG cannot be used or yields negative results or when the tumor remains elusive, positron emission tomography with 18F-fluorodeoxyglucose may be used. The latter test offers greater sensitivity and possibly specificity than MIBG, especially during investigation for a metastatic pheochromocytoma.

Intraoperative Management: What are the options for anesthetic management and how to determine the best technique?

A major drawback of intraoperative epidural blockade is the unpredictable risk of hypotension after removal of the tumor. Such an approach may complicate the perioperative hemodynamic course

b. General Anesthesia

Preoperative. Anxiety before surgery should be treated. In North America, the popular premedication is intravenous or oral midazolam. Since most children have an intravenous catheter during their preparation for surgery, IV midazolam (0.1 mg/kg) can be administered before separating from the parents.

General anesthesia is required for this surgery because tumor resection requires a laparotomy or a laparoscopic approach. Induction of anesthesia may be undertaken with IV lidocaine, propofol and rocuronium. Anesthetics that have a sympathomimetic action (eg., ketamine) are best avoided. Steroidal muscle relaxants (eg., vecuronium), benzodiazepines, opioids and inhalational anesthetics may be used. Some have suggested succinylcholine may trigger a sympathetic response via fasciculations, although the evidence for such a response is weak. Surges in blood pressure may be managed by dosing with propofol, increasing the concentration of the relatively insoluble anesthetic, desflurane or vasodilators. However, abrupt increases or decreases in the desflurane concentration should be preceded by a loading dose of opioids to attenuate or prevent centrally-mediated sympathetic responses to the desflurane. Isoflurane is an equally effective vasodilators as desflurane during periods of hypertension.

6. What is the author's preferred method of anesthesia technique and why?

Prophylactic antibiotics are indicated as per any other abdominal surgery in children.

Most pheochromocytomas are resected using an open laparotomy approach, although more recently laparoscopic surgery has been performed. The latter approach should result in briefer surgery and a more rapid recovery. However, insufflation of the abdomen with carbon dioxide may precipitate a sympathetic response and a decrease in venous return. If the child was not euvolemic before insufflating the abdomen, a rapid decrease in venous return and blood pressure may result. This should be treated aggressively using balanced salt solutions. If insufflation of carbon dioxide triggers a sympathetic response, an IV bolus of propofol should be administered, the concentration of inhaled anesthetic increased and antihypertensives administered as needed. Contraindications to laparoscopic surgery include large tumors (>15 cm), coagulopathy and invasive metastatic disease

For laparotomy, an epidural catheter may be sited after induction of anesthesia and dosed only for perioperative analgesia after the tumor has been removed. This eliminates the contribution of the epidural analgesic to hypotension that may occur. If an epidural is not medically indicated or the parents refuse, then a patient-controlled analgesia.

i. Hypertension can occur during the surgery, before or during manipulation of the tumor, in spite of alpha blockade. Measures that may be used to control the blood pressure include increasing the inspired concentration of inhalational anesthetic, IV propofol (bolus or infusion), sodium nitroprusside infusion (0.5-8 mcg/kg/min), IV magnesium sulfate (30 mg/kg loading dose over 30 minutes followed by an infusion of 10 mg/kg/h), alpha blockers (eg., phentolamine) and calcium channel blockers (eg., diltiazam or nicardipine). Cyanide levels may begin to accumulate at sodium nitroprusside infusion rates ≥ 2 mcg/kg/min.

ii. Tachycardia may occur in response to tumor manipulation, antihypertensive treatment or hypovolemia. Cautious use of beta-blockers is advised particularly in the presence of myocardial dysfunction. The preferred beta-blocker is esmolol because of its very brief duration of action. Note also that reactive hypoglycemia may occur after removal of the tumor, an effect that may be exacerbated by beta-blockade.

iii. Hypotension can occur after the tumor has been removed and may continue for several days postoperatively. This arises from the sudden removal of the source of catecholamines and/or irreversible alpha-blockade by phenoxybenzamine. Supportive treatment with fluids and vasopressors may be effective.

iv. Pulmonary edema. Fluid overload and left ventricular failure may present with the sudden onset of hemoglobin desaturation, increased airway pressures and pulmonary edema fluid in the tracheal tube. This should be prevented by the careful and judicious administration of balanced salt solution throughout the surgery and the avoidance of myocardial depressants. In the presence of a cardiomyopathy, it may be prudent to have a measure of central venous pressure or a transesophageal echocardiography to assess for evidence of left ventricular decompensation during surgery.

v. Reactive hypoglycemia may occur upon removal of the source of catecholamines and relatively excess insulin levels. Blood glucose concentrations should be measured postoperatively until stabilized.

vi. If bilateral adrenalectomy has been performed, steroid replacement may be required postoperatively. It is possible that after such surgery the lack of an adequate concentration of steroids contributes to the finding of hypotension, the much more common cause for the hypotension is hypovolemia.

a. Neurologic:

N/A

b. If the patient is intubated, are there any special criteria for extubation?

What level bed acuity is appropriate? These children should be admitted to a high-intensive care monitored setting for postoperative day one or two to ensure the child maintains hemodynamic stability and effective analgesia. Thereafter, the child may be discharged to a ward.

What are common postoperative complications, and ways to prevent and treat them? Postoperative complications are identical to intraoperative complications: hypotension, hypovolemia, hypertension and hypoglycemia. Hypotension and hypovolemia should be treated with aggressive balanced salt solutions and alpha adrenergic agonists, if a competitive alpha blocking agent was used. Hypertension should be treated with the agents listed above. Hypoglycemia should be managed using a glucose infusion sufficient to maintain the plasma glucose concentration in the normal range.

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